Ion channels constitute a relatively small class of pharmaceutical targets, in part because ion channel screening assays have been difficult to automate and format for high throughput. However, recent advances in electrophysiology (P. B. Bennett et al., Trends in Biotech (2003) 21(12):563-69; C. Wood et al., Drug Disc Today (2004) 9(10):434-41) have rekindled interest in ion channels as targets for drug discovery. A number of ion channels have been linked to inherited diseases, leading to the study of ion channel modulators for the treatment and prevention of disease (D. Owen et al., Drug Disc World (2002) 48-61).
HERG is an ion channel of particular interest to the pharmaceutical industry, although as a safety/toxicology problem rather than a target for developing modulators (ICH S7B Guidance for Industry, October 2005; J. I. Vandenberg et al., Trends Pharm Sci (2001) 22(5):240-46). The voltage-gated hERG potassium channel contributes to the rapidly-activating delayed rectifier potassium current (IKr) of the cardiac action potential. Drug interaction with the hERG potassium channel has been implicated in electrocardiogram QT interval prolongation and the cardiac arrhythmia known as Torsades de Pointes (“TdP”; see C. E. Chiang and D. M. Roden, J Am Coll Cardiol (2000) 36(1):1-12.; D. M. Roden, N Eng J Med (2004) 350:1013-22.). TdP can be fatal, and the risk of inducing it has led to withdrawal and non-approval of pharmaceutical products.
High throughput screening of drug candidates to determine their possible effect on hERG has proven to be difficult, based in large part on the unavailability of a stable cell line that expresses hERG at sufficient surface concentrations, and is a suitable subject for high throughput ion flow measurement instruments.